1. Field of the Invention
The present invention relates to novel urea compounds of Formula I, compositions comprising said compounds, and the use of a compound of Formula I to treat a protein kinase-mediated disease or inhibit a protein kinase.
2. Background Art
Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Protein kinases are involved in signal transduction. Protein kinases are usually categorized into five classes with the two major classes being, tyrosine kinases and serine/threonine kinases. For many biological responses, multiple intracellular kinases are involved, and an individual kinase can be involved in more than one signaling event. These kinases are often cytosolic and can translocate to the nucleus or the ribosomes where they can affect transcriptional and translational events, respectively.
Overproduction of cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α) is implicated in a wide variety of inflammatory diseases, including rheumatoid arthritis (RA), psoriasis, multiple sclerosis, inflammatory bowel disease, endotoxin shock, osteoporosis, Alzheimer's disease, and congestive heart failure, among others (see, e.g., Henry et al., Drugs Future, 24:1345-1354 (1999) Salituro et al., Curr. Med. Chem., 6:807-823 (1999)). There is convincing evidence in human patients that protein antagonists of cytokines, such as, for example, monoclonal antibody to TNF-α, soluble TNF-α receptor-Fc fusion protein (etanercept, or Enbrel®) and IL-1 receptor antagonists, can provide effective treatment for chronic inflammatory diseases.
TNF-α is a protein whose synthesis occurs in many cell types in response to an external stimulus, such as, for example, a mitogen, an infectious organism, or trauma. Signaling from the cell surface to the nucleus proceeds via several intracellular mediators including kinases that catalyze phosphorylation of proteins downstream in the signaling cascade. Important mediators for the production of TNF-α include the mitogen-activated protein (MAP) kinases, and in particular, p38 kinase.
p38 kinases are activated in response to various stress stimuli, including, but not limited to, proinflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock. Four isoforms of p38 have been described. The α and β forms are expressed in inflammatory cells and are considered to be key mediators of TNF-α production. Inhibition of the enzymes p38α and β in cells results in reduced levels of expression of TNF-α, and such inhibitors are effective in animal models of inflammatory disease.
Small molecule inhibitors of p38 are expected to have several advantages over protein inhibitors of TNF-α or IL-1. p38 inhibitors can not only block the production of TNF-α and IL-1, but can also directly interfere with many of their secondary biological effects. In addition, small molecule inhibitors are unlikely to induce immune reactions commonly associated with the administration of proteins. A small molecule inhibitor of p38 would have less chance of being inactivated after oral administration; a major drawback of peptides is their degradation upon oral administration. Thus, there remains a need for compounds which are inhibitors of a p38 kinase, in particular a p38α kinase.